Silylated acetylcholinesterase inhibitors

ABSTRACT

PCT No. PCT/US94/00720 Sec. 371 Date Jul. 18, 1995 Sec. 102(e) Date Jul. 18, 1995 PCT Filed Jan. 25, 1994 PCT Pub. No. WO94/19356 PCT Pub. Date Sep. 1, 1994.Fluorinated silylated aromatic compounds, their intermediates, methods of use in treating diseases associated with deficiencies of cholinergic transmission in the central nervous system and methods for their preparation are disclosed.

This application is a 371 of PCT/US96/0672 filed Jan. 25, 1994.

This invention relates to fluorinated silylated aromatic compounds,their intermediates, methods of use in treating diseases associated withdeficiencies of cholinergic transmission in the central nervous systemand methods for their preparation.

Compounds of the present invention have the following Formula I:##STR1## stereoisomers or mixtures thereof, or pharmaceuticallyacceptable salts thereof, wherein:

each of Z and Z' are independently H or F, provided that at least one ofZ or Z' is F;

Q is ##STR2## X is H, Br, Cl, F or CF₃ ; Y is H, OH, (C₁₋₆) alkyl,--(CH₂)_(m) OR₅, hydroxy(C₁₋₆) alkyl, (CH₂)_(n) NR₆ R₆ ', azido, CN, CO₂R₄, COR₆, SO₃ H, Br, Cl, F, NO₂ or --(CH₂)_(n') SiR₁ 'R₂ 'R₃ ', providedthat when both Z and Z' are F then Y is H or F;

R₁, R₂, R₃, R₁ ', R₂ ' and R₃ ' are each independently C₁₋₁₀ alkyl or(CH₂)_(n") aryl;

R₄ is H, (C₁₋₁₀) alkyl, phenyl, benzyl or phenethyl;

R₅ is H, (C₁₋₁₀) alkyl, benzyl or phenethyl;

R₆ and R₆ ' are independently hydrogen or C₁₋₁₀ alkyl;

m is an integer of 0, 1, 2, 3 or 4; and

n, n' and n" are each independently an integer of 0, 1 or 2.

The compounds of the present invention are used to treat patients havingconditions responsive to the acetylcholin-esterase-inhibiting propertiesof the present compounds such as in the treatment of DegenerativeDementias.

The terms "(C₁₋₆) alkyl" and "(C₁₋₁₀) alkyl" mean straight or branchedchain alkyl radicals containing respectively from 1 to 6 carbon atomsand from 1 to 10 carbon atoms, including, but not limited to, methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl,n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl,2,2-dimethylpropyl, n-hexyl and so on. Likewise, the terms "(CH₂)_(n) "or "(CH₂)_(m) " may represent alkylene chains which may be branched orstraight-chained.

"Hydroxy (C₁₋₆) alkyl" means a (C₁₋₆) alkyl group having from 1 to 3hydroxy substituents thereon. Preferably, there is only one hydroxysubstituent at the alpha position (attached to the carbon atom which isdirectly attached to the phenyl).

"Ts" or "tosyl" means ##STR3## Tosyl derivatives mean ##STR4## wherein Ris C₁₋₆ alkylene.

"Aryl" includes both carbocyclic and heterocyclic moieties of whichphenyl, pyridyl, indolyl, indazolyl, furyl and thienyl are of primaryinterest; these moieties being inclusive of their position isomers suchas, for example, 2-, 3-, or 4-pyridyl, 2- or 3-furyl and thienyl, 1-,2-, or 3-indolyl or the 1- and 3-indazolyl, as well as the dihydro andtetrahydro analogs of the furyl and thienyl moieties. Also includedwithin the term "aryl" are such fused carbocyclic moieties aspentalenyl, indenyl, naphthalenyl, azulenyl, heptalenyl,acenaphthylenyl, fluorenyl, phenalenyl, phenanthrenyl, anthracenyl,acephenanthrylenyl, aceanthrylenyl, triphenylenyl, pyrenyl, chrysenyland naphthacenyl. Also included within the term "aryl" are such otherheterocyclic radicals as 2- or 3-benzo[b]thienyl, 2- or3-naphtho-[2,3-b]thienyl, 2- or 3-thianthrenyl, 2H-pyran-3-(or 4- or5-)yl, 1-isobenzofuranyl, 2H-chromenyl-3-yl, 2- or 3-phenoxathiinyl, 2-or 3-pyrrolyl, 4- or 3-pyrazolyl, 2-pyrazinyl, 2-pyrimidinyl,3-pyridazinyl, 2-indolizinyl, 1-isoindolyl, 4H-quinolizin-2-yl,3-isoquinolyl, 2-quinolyl, 1-phthalazinyl, 1,8-naphthyridinyl,2-quinoxalinyl, 2-quinazolinyl, 3-cinnolinyl, 2-pteridinyl,4aH-carbazol-2-yl, 2-carbazolyl, β-carbolin-3-yl, 3-phenanthridinyl,2-acridinyl, 2-perimidinyl, 1-phenazinyl, 3-isothiazolyl,2-phenothiazinyi, 3-isoxazolyl, 2-phenoxazinyl, 3-isochromanyl,7-chromanyl, 2-pyrrolin-3-yl, 2-imidazolidinyl, 2-imidazolin-4-yl,2-pyrazolidinyl, 3-pyrazolin-3-yl, 2-piperidyl, 2-piperazinyl,1-indolinyl, 1-isoindolinyl, 3-morpholinyl, benzo[h]isoquinolinyl, andbenzo[b]furanyl, including the position isomers thereof except that theheterocyclic moieties cannot be attached directly through their nitrogenatoms. Aryl groups can be substituted or unsubstituted with one, two orthree substituents independently selected from C₁₋₆ alkyl, haloalkyl,alkoxy, thioalkoxy, aminoalkylamino, dialkylamino, hydroxy, halo,mercapto, nitro, carboxaldehyde, carboxy, carboalkoxy and carboxamide.

R₁, R₂, R₃, R₁ ', R₂ ', and R₃ ' are each independently selected fromC₁₋₁₀ alkyl or (CH₂)_(n") aryl which means that, for example, R₁ couldbe benzyl while R₂ is methyl. In other words, none of R₁, R₂, R₃, R₁ ',R₂ ', or R₃ ' have to be the same moiety, although this may be the case.

"Stereoisomers" for the compounds of Formula I is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes mirror image isomers (enantiomers),geometric isomers (cis/trans), and isomers of compounds with more thanone chiral center that are not mirror images of one another(diastereoisomers), whichever forms are applicable to the compound.

The pharmaceutically acceptable salts of the compounds of Formula Iinclude salts formed with non-toxic organic or inorganic acids such as,for example, from the following acids: hydrochloric, hydrobromic,sulfonic, sulfuric, phosphoric, nitric, maleic, fumaric, benzoic,ascorbic, pamoic, succinic, methanesulfonic, acetic, propionic,tartaric, citric, lactic, malic, mandelic, cinnamic, palmitic, itaconicand benzenesulfonic.

The term "patient" refers to a warm-blooded animal, such as for examplerats, mice, dogs, cats, guinea pigs, primates and humans. "Treating" apatient means to prevent or alleviate the patient's disease orcondition.

The term "Degenerative Dementia" as used herein means senile dementia,presenile dementia, degenerative dementia of the Alzheimer's type (whichincludes Alzheimer's Disease) and other types of progressivelydeteriorating organic mental syndromes in which there is impairment inshort-term and long-term memory. The Degenerative Dementia can be mild(impairment of work or social activities but able to live alone),moderate (some degree of supervision needed), or severe (continualsupervision required).

Impairment in short-term memory is the inability to learn newinformation and may be demonstrated by, for example, the patient'sinability to remember three objects after five minutes. Long-term memoryimpairment is the inability to remember information that was known inthe past and may be indicated by, for example, the patients' inabilityto remember past personal information such as their birthplace, address,occupation, what happened yesterday, etc., or the inability to rememberfacts of common knowledge. There is typically impairment in abstractthinking, impairment in judgment, personality changes or otherdisturbances of higher cortical functions.

The preparation of the compounds of Formula I may be accomplished in avariety of methods depending upon the specific combinations of variablesubstituents. The following schemes illustrate only one way thesecompounds may be made. Other analogous chemical reactions and proceduresmay be utilized which may be known to those skilled in the art. ##STR5##

All substituents are as previously defined unless otherwise stated. Allstarting materials are either commercially available or can be readilyprepared by those skilled in the art.

Step Aa: A₁ →A₂

The reaction involves the treatment of 4-bromo-1-fluoro benzene withClSiR₁ R₂ R₃ in the presence of one equivalent of magnesium in asuitable solvent such as diethylether or tetrahydrofuran at the refluxtemperature of the mixture. The silyl derivatives ClSiR₁ R₂ R₃ areobtained from tetrachlorosilane (SiCl₄) and successive alkylations withorganomagnesium halide derivatives of the appropriate R₁, R₂ and R₃substituents. For example, SiCl₄ is reacted with R₁ Mg halides toproduce R₁ SiCl₃ compounds which are reacted with R₂ Mg halides toproduce R₁ R₂ SiCl₂ compounds which are reacted with R₃ Mg halides toproduce R₁ R₂ R₃ SiCl compounds.

Step Ab: A₂ →A₃

The 4-fluorotrialkylsilylphenyl compounds are converted to their lithiumsalts by reaction with an alkyllithium reagent at -50° C. intetrahydrofuran and those intermediates to the desired products byreaction with two equivalents of the appropriate ester (XCF₂ CO₂ R, withR being preferably ethyl or methyl and X being any suitable halogen) oracid lithium salt (XCF₂ CO₂ Li) followed by hydrolysis with aqueousammonium chloride.

Step Ac: A₃ →A₄

The ketones are converted to alcohols preferably by using sodiumtetraborohydride or sodium cyanoborohydride in ethanol, followed byhydrolysis with aqueous ammonium chloride.

Step Ad: A₄ →A₅

The alcohols are esterfied preferably with an acyl chloride [(ClCOR₄)]in the presence of triethylamine in a solvent such as dichloromethane.

Step Ae: A₂ →A₆

Following Step Ab the lithium salt intermediates are reacted with carbondioxide to produce carboxylic acids.

Step Af: A₆ →A₇

Acids are reacted with isobutylchloroformate in the presence oftriethylamine or N-methyl morpholine in tetrahydrofuran to form mixedanhydrides. Addition of molar equivalent amount ofN,O-dimethylhydroxylamine to the anhydrides gives dimethylhydroxamicacid derivatives.

Step Ag: A₇ →A₈

Dimethyl hydroxamic acid derivatives are converted to thepentafluoroketones preferably by treatment with a pentafluoroethyl aniongenerated insitu by contacting pentafluoroethyl iodide with amethyllithium-lithium bromide complex in an inert solvent, preferablydiethyl ether. Hydrolysis is performed with aqueous ammonium chloride.

Reference is later made herein to a combination of steps of Scheme A asfollows:

Sa=steps Ab+Ac+Ad

Sb=steps Ae+Af+Ag+Ac+Ad ##STR6## Step Ba: B₁ (A₆)→B₂

Carboxylic acids A₆ are reacted with excess of thionyl chloride atreflux temperature to produce acyl chlorides which are reacted withsodium azide at 0° C. in acetone-water to produce acyl azides which areheated in benzene or toluene at reflux temperature and then treated withhydrochloric acid at reflux temperature to produce amine hydrochloridesalts B₂.

Step Bb: B₂ →B₃

Amine hydrochloride salts B₂ are converted to their free amines withaqueous sodium hydroxide and then treated with two equivalents ofalkyllithium followed by two equivalents of chlorotrimethylsilane indiethyl ether or tetrahydrofuran at -60° C. to producebistrimethylsilylated amines B₃.

Step Ab: B₃ →B₄ →B₅

Conversion of B₃ to B₄, then to B₅ by Steps Ab and Ac as previouslydescribed.

Step Ad': B₅ →B₆

Following the procedure described in Step Ad the resulting esters aretreated with a normal solution of hydrochloric acid.

Step Bc: B₆ →B₇ and B₁₇ →B₁₈

When Y^(B) =Cl, CN, or N₃ : The amine hydrochloride salts (B₆ and B₁₇)are treated with sodium nitrite in water to produce diazonium saltswhich are heated with cuprous chloride to produce chloroderivatives, ortreated with cuprous cyanide to produce nitrile derivatives, or treatedwith sodium azide to produce azides.

When Y^(B) =Br: The amine hydrochloride salts (B₆ and B₁₇) are convertedto their free amines with aqueous sodium bicarbonate. The free aminesare dissolved in aqueous hydrobromic acid, treated with sodium nitriteand then with copper powder to produce bromide derivatives.

When Y^(B) =F or NO₂ : The amine hydrochloride salts (B₆ and B₁₇) areconverted to their free amines with aqueous sodium bicarbonate. The freeamines dissolved in aqueous fluoroboric acid are treated with sodiumnitrite. The diazonium fluoroborate salts are filtered and dried. Theyare then heated to produce fluoro derivatives or treated with sodiumnitrite in the presence of copper powder to produce nitro derivatives.

When Y^(B) =OH: After conversion of the amine hydrochloride salts (B₆and B₁₇) to their free amines, the amines are dissolved in aqueoussulfuric acid, diazoted with sodium nitrite and heated to produce phenolderivatives.

When y^(B) =SO₃ H: After conversion of the amine hydrochloride salts totheir free amines, the amines are dissolved in an aqueous mixture ofsulfuric acid and phosphoric acid, diazoted with sodium nitrite andtreated with sulfur dioxide. The reaction mixture is poured ontohydrated ferrous sulfate and copper powder to produce sulfinic acid.

Step Bd: B₇ →B₈ and B₁₈ →B₁₉

Esters B₇ and B₁₈ are hydrolized with lithium hydroxyde in aqueousdimethoxyethane to produce alcohols B₈ and B₁₉.

Step Be: B₈ →B₉ and B₁₉ →B₂₀

Alcohols B₈ and B₁₉ are oxidized with pyridinium dichromate or withDess-Martin periodinane oxidant in dichloromethane or with the SwernReaction to produce ketones B₉ and B₂₀.

Steps Ab', Ac' and Ag': respectively B₃ →B₁₀ ; B₄ →B₁₁ ; and B₁₃ →B₁₄

Procedure Ab, Ac or Ag is used as described previously, excepthydrolysis is performed with a normal solution of hydrochloric acid.

Step Bf: B₈ or B₁₉ →B₂₁

Phenol derivatives B₈ or B₁₉ are converted to their sodium or potassiumsalt with sodium or potassium hydroxide, or sodium or potassiumcarbonate in water or acetone and reacted with alkyl bromide or iodideto produce C₁₋₆ alkoxy derivatives.

Step Bg: B₈ or B₁₉ →B₂₃

Nitrile derivatives are heated in aqueous hydrochloric acid to produceacids (R₄ =H) or treated with an alcohol saturated with dry hydrochloricacid followed by hydrolysis with aqueous sodium bicarbonate to produceesters' (R₄ different from H). ##STR7## Step Ca: C₁ (A₂)→C₂ :

Following the procedure described in Step Ab the lithium salts aretreated with chlorotrisubstituted silane to produce bis-silylatedderivatives C₂.

Step Cb: C₁ →C₄ :

Following the procedure described in Step Ab the lithium salts aretreated with paraformaldehyde to produce benzyl alcohol derivatives C₄.

Step Cc: C₄ →C₅ :

Benzyl alcohols are heated with phosphorous tribromide to produce benzylbromide derivatives C₅.

Step Cd: C₁ →C₈ :

Following the procedure described in Step Ab the lithium salts aretreated with ethylene oxide to produce phenethyl alcohol derivatives C₈.

The remaining reactions indicate the steps previously described whichare used. ##STR8## Step Da: D₁ =A₂ →D₂ or D₁₁ :

Following the procedure described in Step Ab the lithium salts aretreated with paraformaldehyde or aldehydes or ketones to produce benzylalcohol derivatives D₂ or D₁₁.

Step Db: D₂ →D₃ and D₁₁ →D₁₄

Benzyl alcohol derivatives D₂ or D₁₁ are treated withp-toluenesulfonylchloride in pyridine at 0° C. to produce tosylderivatives D₃ or D₁₄.

Step Dc: D₃ →D₄ and D₁₄ →D₁₅

Tosyl derivatives are reduced with lithium aluminum hydride indi-n-butyl ether to produce alkyl derivatives D₄ or D₁₅.

Step Dc':

Alternatively non-branched alkyl derivatives D₄ are produced by reactionof the lithium salt of A₂ (prepared as described in Step Ab) with anon-substituted alkyl bromide or iodide.

Step Dd: D₂ →D₆

Benzyl alcohol derivatives D₂ are reacted with phthalimide in thepresence of equimolar amounts of diethyl azodicarboxylate andtriphenylphosphine in tetrahydrofuran to produce phtalimide derivativeswhich are then treated with hydrazine hydrate in ethanol or methanol toproduce amine derivatives D₆.

Step De: D₁₁ →D₁₂

Benzyl alcohol derivatives D₁₁ are heated with trimethyl aluminum toproduce alkyl derivatives D₁₂.

Step Df: D₆ →D₁₉

Amine derivatives D₆ are reacted with di-tert-butyl dicarbonate with oneequivalent of triethylamine in dichloromethane to produce N-Bocderivatives D₁₉.

Step Dg: D₁₉ →D₂₀

N-Boc derivatives D₁₉ are reacted with one equivalent of sodium hydridein tetrahydrofuran. The sodium salt intermediates are reacted with abromo or iodo derivative of R₆ followed by hydrolysis with aqueoushydrochloric acid, Amine derivatives D₂₀ are purified as their freebases after neutralization of the aqueous phase.

Step Dh: D₂₀ →D₂₂

Following Step Bb amine derivatives D₂₀ are treated with one equivalentof alkyl lithium reagent followed by one equivalent ofchlorotrimethylsilane to produce N-trimethylsilylamine derivatives D₂₂.

Step Di: D₂₀ →D₂₁

Following Step Dg amine derivatives D₂₀ are treated with one equivalentof sodium hydride and one equivalent of bromo or iodo derivative of R₆followed by hydrolysis with water to produce amine derivatives D₂₁.

Step Dj: D₁₀ (D₁₈)→D₂₄ and D₂₇ →D₂₈

Methylbenzyl ether derivatives D₉ (D₁₇) or D₂₇ are treated with borontribromide or trimethylsilyliodide in dichloromethane to produce benzylalcohols derivatives D₂₄ or D₂₈.

Other steps not specifically described are defined in the scheme asusing steps previously described. ##STR9##

Step Ca: The same reaction is used as previously described in Scheme C,but with the starting materials shown in this scheme.

Steps Sa, Sb: Using the starting material shown in Scheme E1, thereaction is as described in Scheme A. ##STR10##

All reactions are as previously defined herein using the compounds shownabove. ##STR11##

Step Ea: 4-Fluoro-1-bromobenzene is reacted with one equivalent ofmagnesium in diethyl ether or tetrahydrofuran. To this Grignardintermediate is added paraformaldehyde or aldehyde or ketone to producebenzyl alcohol derivatives. ##STR12##

Step Ja: 2,4-Difluoro-1-bromobenzene or 2,4,5-trifluoro-1-bromobenzeneis treated with one equivalent of an alkyl-lithium reagent in diethylether or tetrahydrofuran at -78° C. The lithium salt intermediate isreacted with a chlorotrisubstituted silane at -50° C. to produce thecorresponding silylated derivatives.

Steps Sa, Sb: As previously described using the compounds shown inScheme J.

EXAMPLE 1

2,2,2-Trifluoro-1-(3-Trimethylsilyl-6-fluoro)phenyl ethanone ##STR13##STEP A: 4-TRIMETHYLSILYL-1-FLUOROBENZENE

A solution of 17.5 g (100 mmol) of 4-bromo-1-fluorobenzene and 10.86 g(100 mmol) of chlorotrimethylsilane in 100 ml of tetrahydrofuran isadded dropwise in 1.5 hour on 2.43 g (1.00 mg-atoms) of magnesium in 50ml of tetrahydrofuran at reflux. Then the reaction mixture is refluxed18 hours, cooled to 0° C. and hydrolized by the addition of 100 ml of 3NHCl. The organic layer is separated, washed with brine, dried over MgSO₄and concentrated. 4-trimethyl-1-fluorobenzene is distilled to yield13.45 g (80%); b.p. 64°-65° C./15 mmHg.

STEP B:

2,2,2-TRIFLUORO-1-(3-TRIMETHYLSILYL-6-FLUORO)PHENYL ETHANONE

To a solution of 8.40 g (50 mmol) of 4-trimethylsilyl-1-fluorobenzene in50 ml of tetrahydrofuran at -50° C. is added dropwise 33.33 ml (50 mmol)of 1.5M n-butyl lithium in hexane. The reaction mixture is stirred 2hours and then cooled to -78° C. A solution of 14.20 g (100 mmol) ofethyl trifluoroacetate in 40 ml of tetrahydrofuran is added dropwise andthe reaction mixture is stirred 1 hour at -78° C. The cooling bath isremoved and when the temperature rose to 0° C., 100 ml of 3N HCl isadded. The organic layer is separated, washed with brine, dried overMgSO₄ and concentrated. Chromatography on silica gel (2% of ethylacetate in petroleum ether) followed by distillation afforded 1.87 g(14%) of title compound; b.p. 120° C./14 mmHg.

EXAMPLE 2

2,2,2-Trifluoro-1-(3-trimethylsilyl-6-fluoro)phenyl ethanol ##STR14##

To a solution of 0.67 g (2.55 mmol) of2,2,2-trifluoro-1-(3-trimethyl-6-fluoro)phenyl ethanone in 5 ml ofethanol at 0° C. is added 0.97 g (2.55 mmol) of sodium borohydride. Thereaction mixture is stirred 1 hour at room temperature, cooled to 0° C.and hydrolized with 1.64 g (30.65 mmol) of ammonium chloride in 30 ml ofwater. The crude product is extracted with diethyl ether (2×30 ml), theorganic layer is washed twice with brine, dried over MgSO₄ andconcentrated. Chromatography on silica gel (5% of ethyl acetate inpetroleum ether) followed by distillation afforded 0.54 g (80%) of thetitle compound; b.p. 145° C./19 mmHg.

EXAMPLE 3

2,2,2-Trifluoro-1-(2-fluoro-5-dimethylethylsilyl)phenyl ethanone##STR15## STEP A: 4 -DIMETHYLETHYLSILYL-1-FLUOROBENZENE

Following the procedure described in Step A of the Example 1, titlecompound is obtained in 37% yield; b.p. 85°-87° C./17 mmHg.

STEP B:

2,2,2-TRIFLUORO-1-(2-FLUORO-5-DIMETHYLETHYLSILYL)PHENYL ETHANONE

Following the procedure described in Step B of the Example 1, titlecompound is obtained in 19% yield; b.p. 135° C./14 mmHg.

EXAMPLE 4

2,2,2-Trifluoro-1-(2-fluoro-3-trimethylsilyl)phenyl ethanone ##STR16##STEP A 2-TRIMETHYLSILYL-1-FLUOROBENZENE

To a solution of 4.8 g (50 mmol) of fluorobenzene in 50 ml oftetrahydrofuran at -50° C. is added dropwise 37.60 ml (50 mmol) of 1.33Mn-butyl lithium hexane. The reaction mixture is stirred 6 hours whilethe temperature is kept between -40° C. and -50° C. To the solution isadded 5.43 g (50 mmol) of chlorotrimethylsilane in 10 ml oftetrahydrofuran. The reaction mixture is stirred 3 hours at -50° C., 15hours at room temperature and hydrolized with 5.35 g (100 mmol) ofammonium chloride in 50 ml of water. The organic layer is separated,washed with brine, dried over MgSO₄ and concentrated. Crude material isdistilled in vacuo, yielding 0.37 g (3%); b.p. 42° C./15 mmHg.

STEP B:

2,2,2-TRIFLUORO-1-(2-FLUORO-3-TRIMETHYLSILYL)PHENYL ETHANONE

To a solution of 0.37 g (1.6 mmol) of 2-trimethylsilyl-1-fluorobenzenein 3.5 ml (1.6 mmol) is added 1.6M n-butyl lithium in hexane. Thereaction mixture is stirred 6 hours at -50° C., cooled to -78° C. and asolution of 0.23 g (1.6 mmol) of ethyl trifluoroacetate in 2 ml oftetrahydrofuran is added. The reaction mixture, is stirred one hour at-78° C., 15 hours at room temperature and hydrolized with 5 ml of 1NHCl. The organic layer is separated, washed with brine, dried over MgSO₄and concentrated. Chromatographon silica gel (5% of ethyl acetate inpetroleum ether) afforded 0.12 g (28%) of the title compound.

EXAMPLE 5

2,2,2-Trifluoro-1-(2,6-difluro-3-trimethylsilyl)phenyl ethanone##STR17## STEP A: 2,4-DIFLUORO-1-TRIMETHYLSILYLBENZENE

To a solution of 5.8 g (30 mmol) of 2,4-difluoro-1-bromobenzene in 40 mlof tetrahydrofuran at -78° C. is added dropwise 20 ml (30 mmol) of 1.5Mn-butyl lithium in hexane. The reaction mixture is stirred 10 minutes at-78° C. Then a solution of 3.26 g (30 mmol) of chlorotrimethylsilane in15 ml of tetrahydrofuran is added dropwise and the reaction mixture isstirred 7 hours between -60° C. and -50° C. To the reaction mixture isadded 4.8 g (90 mmol) of ammonium chloride in 30 ml of water and theorganic layer is separated, washed with brine, dried over MgSO₄ andconcentrated. Title compound is purified by distillation.

STEP B:

2,2,2-TRIFLUORO-1-(2,6-DIFLUORO-3-TRIMETHYLSILYL)PHENYL ETHANONE

Title compound is prepared as described in step B of the Example 4 andpurified by distillation.

EXAMPLE 6

2,2,2-Trifluoro-1-(2-fluoro-3-methoxymethyl-5-trimethyl-silyl)phenylethanone ##STR18## STEP A:2-HYDROXYMETHYL-5-TRIMETHYLSILYL-1-FLUOROBENZENE

To a solution of 3.36 g (20 mmol) of 4-fluoro-1-trimethylsiyl benzene in20 ml of tetrahydrofuran at -50° C. is added dropwise 13.33 ml (20 mmol)of 1.5M n-butyl lithium in hexane. The reaction mixture is stirred 6hours while the temperature was kept between -50° C. and -60° C. To thesolution was added 1.20 g (40 mmol) of paraformaldehyde by portion at-78° C. The reaction mixture is stirred one hour at -78° C., 15 hours atroom temperature and hydrolized with 20 ml of 3N HCl. The organic layeris separated, washed with brine, dried over MgSO₄ and concentrated. Thetitle compound is purified by distillation.

STEP B:

2-METOXYMETHYL-5-TRIMETHYLSILYL-1-FLUOROBENZENE

A solution of 1.98 g (10 mmol) of2-hydroxymethyl-5-trimethylsilyl-1-fluorobenzene in 10 ml oftetrahydrofuran is added dropwise on a mixture of 0.24 g (10 mmol) ofsodium hydride in 10 ml of tetrahydrofuran at 0° C. The reaction mixtureis stirred 3 hours at room temperature and cooled to 0° C. A solution of1.42 g (10 mmol) of iodomethane in 10 ml of tetrahydrofuran is addeddropwise and the reaction mixture is stirred 15 hours at roomtemperature. A solution of 1.60 g (30 mmol) of ammonium chloride in 10ml of water is added, the organic layer is separated, washed with brine,dried over MgSO₄ and concentrated. The title compound is purified bydistillation.

STEP C:

2,2,2-TRIFLUORO-1-(2-FLUORO-3-METHOXYMETHYL-5-TRIMETHYLSILYL)PHENYLETHANONE

Title compound is prepared as described in step B of Example 4.

EXAMPLE 7

2,2,2-Trifluoro-1-(2-fluoro-3-hydroxymethyl-5-trimethylsilyl)phenylethanone ##STR19##

To a solution of 1.54 g (5 mmol) of2,2,2-trifluoro-1-(2-fluoro-3-methoxymethyl-5-trimethylsilyl)phenylethanone in 10 ml of dichloromethane at -78° C. is added dropwise 5 ml(5 mmol) if 1M boron tribromide in dichloromethane. Cooling bath isremoved and the reaction mixture is stirred one hour at roomtemperature. Then 2 ml of methanol is added dropwise, followed by 10 mlof water. The organic layer is separated, washed with brine, dried overMgSO₄ and concentrated. Title compound is recrystallized fromisopropanol.

EXAMPLE 8

2,2,2-Trifluoro-1-(2-fluoro-3-n-butyl-5-trimethylsilyl)phenyl ethanone##STR20## STEP A: 2-n-BUTYL-4-TRIMETHYLSILYL-1-FLUOROBENZENE

To a solution of 3.36 g (20 mmol) of 4-fluoro-1-trimethylsilylbenzene in20 ml of tetrahydrofuran at -50° C. is added dropwise 13.33 ml (20 mmol)of 1.5M n-butyl lithium in hexane. The reaction mixture is stirred 4hours between -40° C. and -50° C. and then 3.68 g (20 mmol) ofn-iodobutane in 10 ml of tetrahydrofuran is added dropwise. The reactionmixture is stirred 4 hours between -40° C. and -50° C., cooling bath isremoved and 20 ml of 1N HCl is added dropwise. The organic layer isseparated, washed with brine, dried over MgSO₄ and concentrated. Thetitle compound is purified by distillation.

STEP B:

2,2,2-TRIFLUORO-1-(2-FLUORO-3-n-BUTYL-5-TRIMETHYLSILYL)PHENYL ETHANONE

Title compound is prepared as described in step B of the Example 4.

EXAMPLE 9

2,2,2-Trifluoro-1-(2-fluoro-3-amino-5-trimethylsilyl)phenyl ethanonehydrochloride ##STR21## STEP A: 2-FLUORO-5-TRIMETHYLSILYL-BENZOIC ACID

To a solution of 8.4 g (50 mmol) of 4-fluoro-1-trimethylsilyl benzene in50 ml of tetrahydrofuran at -60° C. is added dropwise 31.25 ml (50 mmol)of 1.6M n-butyl lithium in hexane and the reaction mixture is stirred 6hours between -50° C. and -60° C. Then the reaction mixture is treatedwith excess of carbon dioxide, cooling bath is removed and 50 ml ofwater is added dropwise. Tetrahydrofuran is removed under reducedpressure and the aqueous solution is extracted twice with 30 ml ofn-hexane. The aqueous layer is acidified with 20 ml of 6N HCl, extractedtwice with 50 ml of ethyl acetate. The organic layers are combined,washed with brine, dried over MgSO₄ and concentrated. Title compound isrecrystallized from isopropanol.

STEP B:

2-FLUORO-5-TRIMETHYLSILYL-ANILINE

A mixture of 2.12 g (10 mmol) of 2-fluoro-5-trimethylsilyl-benzoic acidand 1.78 g (15 mmol) of thionyl chloride is heated 2 hours at 60° C.Then gases and excess of thionyl chloride are removed under reducedpressure. To the crude material dissolved in 10 ml of acetone is addeddropwise 6.5 g (10 mmol) of sodium azide in 10 ml of water and themixture is stirred one hour at 0° C. Acetone is removed under reducedpressure and the acyl azide was extracted with ethyl acetate. Theorganic phase is dried over MgSO₄ and ethyl acetate is removed underreduced pressure. To the acyl azide 20 ml of benzene is added and thereaction mixture is stirred 30 minutes at reflux. Then the solution iscooled to 0° C., 10 ml of concentrated hydrochloric acid is added andthe mixture is heated 30 minutes at reflux. Benzene and water areremoved under reduced pressure and the hydrochloride salt isrecrystallized from isopropanol. To the salt dissolved in 10 ml of wateris added 10 ml of 1N sodium hydroxide and the aqueous mixture isextracted with ethyl acetate. The organic layer is washed with brine,dried over MgSO₄ and concentrated to obtain pure2-fluoro-5-trimethylsilyl-aniline.

STEP C:

2-FLUORO-5-TRIMETHYLSILYL-N,N-(bis-TRIMETHYLSILYL)ANILINE

To a solution of 0.91 g (5 mmol) of 2-fluoro-5-trimethylsilyl-aniline in10 ml of tetrahydrofuran at 0° C. is added dropwise 6.67 ml (10 mmol) of1.5M n-butyl lithium in hexane and 10 minutes later 1.08 g (10 mmol) ofchlorotrimethylsilane in 10 ml of tetrahydrofuran. Cooling bath isremoved and the mixture is stirred one hour at reflux. Solvents areremoved under reduced pressure and title compound is purified bydistillation.

STEP D:

2,2,2-TRIFLUORO-1-(2-FLUORO-3-AMINO-5-TRIMETHYLSILYL)PHENYL ETHANONEHYDROCHLORIDE

TO a solution of 0.98 g (3 mmol) of2-fluoro-5-trimethylsilyl-N,N-(bis-trimethylsilyl)aniline in 6 ml oftetrahydrofuran at -60° C. is added dropwise 2 ml (3 mmol) of 1.5Mn-butyl lithium in hexane. The reaction mixture is stirred 6 hoursbetween -50° C. and -60° C., cooled to -78° C. and a solution of 0.85 g(6 mmol) of ethyl trifluoroacetate in 6 ml of tetrahydrofuran is addeddropwise. The reaction mixture is stirred one hour at -78° C., 15 hoursat room temperature and hydrolized with 10 ml of 3N HCl. Organicsolvents are removed under reduced pressure. The aqueous layer isextracted twice with diethyl ether, basified with 10 ml of 6N sodiumhydroxide, extracted twice with ethyl acetate. The ethyl acetate layersare combined, washed with brine, dried over MgSO₄ and concentrated.Crude material is dissolved in diethyl ether and treated with asaturated solution of HCl in diethyl ether. The hydrochloride salt isfiltered and recrystallized from isopropanol.

It is now established that Alzheimer's disease and other seniledegenerative diseases such as senile dementia are characterized by aselective loss in the cerebral cortex of choline acetyltransferase, theenzyme responsible for the biosynthesis of acetylcholine. There alsoexists a good correlation between memory impairment or dementia and thedecrement in cholinergic transmission. Thus, impaired cholinergictransmission in the central nervous system may be, at least in part,responsible for the symptomatology of Alzheimer's disease and seniledementia. In support to these conclusions such compounds asphysostigmine and 1,2,3,4-tetrahydro-9-aminoacridine (THA), compoundswhich prevent the catabolism of acetylcholine have found a place in thetreatment of Alzheimer's and other senile degenerative diseases. Indeed,it has been recognized that the extent of improvement of cognitivefunctions has been closely related to the degree of inhibition ofacetylcholinesterase.

The compounds of the present invention are useful in treating otherconditions responsive to inhibition of acetylcholinesterase such asMyasthenia Gravis [J. Neurol. Neurosurg. Psychiatry, 46 (10) 1983,929-935, Neurology 42 (6) 1992, 1153-1156], antidotes against poisoningwith organophosphates [see U.S. Pat. No. 5,171,750, Int. J. Pharmacol.Ther. Toxicol. 27 (8) 1989, 367-387], and glaucoma (Arch. Clin. Exp.Ophthalmol. 229 (3), 1991, 252-253).

The compounds of Formula I are pharmacologically active agents capableof inhibiting acetylcholinesterase as demonstrable in standardbiological in vitro and in vivo test procedures. Indeed, based uponstandard laboratory procedures, it is to be shown that the compounds ofFormula I are potent and selective, quasi irreversible inhibitors ofacetylcholinesterase capable of demonstrating advantages over the priorart,, particularly physostigmine, in their use in the treatment ofAlzheimer's disease and senile dementia. The compounds, in general, willexert their acetylcholinesterase inhibitory properties within the doserange of about 0.01 mg to 5 mg per kilogram of body weight for thepreferred compounds.

For pharmacological end-use applications, the compounds of Formula I arepreferentially administered in the form of their pharmaceuticallyacceptable acid addition salts. Of course, the effective dosage of thecompounds will vary according to the individual potency of each compoundemployed, the severity and nature of the disease being treated and theparticular subject being treated. In general, effective results can beachieved by administering a compound at a dosage of about 0.01 mg toabout 20 mg per kilogram of body weight per day, administeredsystemically. Therapy should be initiated at lower dosages. The dosagethereafter may be administered orally in solid dosage forms, e.g.,capsules, tablets, or powders, or in liquid forms, e.g., solutions orsuspensions. The compounds may also be injected parenterally in the formof sterile solutions or suspensions.

In practicing the method of this invention, the active ingredient ispreferably incorporated in a composition comprising a pharmaceuticalcarrier and from about 5 to about 90 percent by weight of a compound ofthe invention or a pharmaceutically-acceptable salt thereof. The term"pharmaceutical carrier" refers to known pharmaceutical excipientsuseful in formulating pharmaceutically active compounds for internaladministration to animals, and which are substantially non-toxic andnon-sensitizing under conditions of use. The compositions can beprepared by known techniques for the preparation of tablets, capsules,elixirs, syrups, emulsions, dispersions and wettable and effervescentpowders, and can contain suitable excipients known to be useful in thepreparation of the particular type of composition desired.

The preferred route of administration is oral administration. For oraladministration the formula I compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, lozenges,melts, powders, solutions, suspensions, or emulsions. The solid unitdosage forms can be a capsule which can be of the ordinary hard- orsoft-shelled gelatin type containing, for example, surfactants,lubricants, and inert fillers such as lactose, sucrose, calciumphosphate, and cornstarch. In another embodiment the compounds of thisinvention can be tableted with conventional tablet bases such aslactose, sucrose, and cornstarch in combination with binders such asacacia, cornstarch, or gelatin, disintegrating agents intended to assistthe break-up and dissolution of the tablet following administration suchas potato starch, alginic acid, corn starch, and guar gum, lubricantsintended to improve the flow of tablet granulations and to prevent theadhesion of tablet material to the surfaces of the tablet dies andpunches, for example, talc, stearic acid, or magnesium, calcium, or zincstearate, dyes, coloring agents, and flavoring agents intended toenhance the aesthetic qualities of the tablets and make them moreacceptable to the patient. Suitable excipients for use in oral liquiddosage forms include diluents such as water and alcohols, for example,ethanol, benzyl alcohol, and the polyethylene alcohols, either with orwithout the addition of a pharmaceutically acceptable surfactant,suspending agent, or emulsifying agent.

The formula I compounds of this invention may also be administeredparenterally, that is, subcutaneously, intravenously, intramuscularly,or interperitoneally, as injectable dosages of the compound in aphysiologically acceptable diluent with a pharmaceutical carrier whichcan be a sterile liquid or mixture of liquids such as water, saline,aqueous dextrose and related sugar solutions, an alcohol such asethanol, isopropanol, or hexadecyl alcohol, glycols such as propyleneglycol or polyethylene glycol, glycerol ketals such as2,2-dimethyl-1,3-dioxolane-4methanol, ethers such as polyethylene glycol400, an oil, a fatty acid, a fatty acid ester or glyceride, or anacetylated fatty acid glyceride with or without the addition of apharmaceutically acceptable surfactant such as a soap or a detergent,suspending agent such as pectin, carbomers, methylcellulose,hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifyingagent and other pharmaceutically acceptable adjuvants. Illustrative ofoils which can be used in the parenteral formulations of this inventionare those of petroleum, animal, vegetable, or synthetic origin, forexample, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil,olive oil, petrolatum, and mineral oil. Suitable fatty acids includeoleic acid, stearic acid, and isostearic acid. Suitable fatty acidesters are, for example, ethyl oleate and isopropyl myristate. Suitablesoaps include fatty alkali metal, ammonium, and triethanolamine saltsand suitable detergents include cationic detergents, for example,dimethyl dialkyl ammonium halides, alkyl pyridinium halides; anionicdetergents, for example, alkyl, aryl, and olefin sulfonates, alkyl,olefin, ether, and monoglyceride sulfates, and sulfosuccinates; nonionicdetergents, for example, fatty amine oxides, fatty acid alkanolamides,and polyoxyethylenepolypropylene copolymers; and amphoteric detergents,for example, alkyl beta-aminopropionates, and 2-alkylimidazolinequarternary ammonium salts, as well as mixtures. The parenteralcompositions of this invention will typically contain from about 0.5 toabout 25% by weight of the formula I compound in solution. Preservativesand buffers may also be used advantageously. In order to minimize oreliminate irritation at the site of injection, such compositions maycontain a non-ionic surfactant having a hydrophile-lipophile balance(HLB) of from about 12 to about 17 . The quantity of surfactant in suchformulations ranges from about 5 to about 15% by weight. The surfactantcan be a single component having the above HLB or can be a mixture oftwo or more components having the desired HLB. Illustrative ofsurfactants used in parenteral formulations are the class ofpolyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The compounds of this invention can also be administered topically. Thiscan be accomplished by simply preparing a solution of the compound to beadministered, preferably using a solvent known to promote transdermalabsorption such as ethanol or dimethyl sulfoxide (DMSO) with or withoutother excipients. Preferably topical administration will be accomplishedusing a patch either of the reservoir and porous membrane type or of asolid matrix variety.

Some suitable transdermal devices are described in U.S. Pat. Nos.3,742,951, 3,797,494, 3,996,934,and 4,031,894. These devices generallycontain a backing member which defines one of its face surfaces, anactive agent permeable adhesive layer defining the other face surfaceand at least one reservoir containing the active agent interposedbetween the face surfaces. Alternatively, the active agent may becontained in a plurality of microcapsules distributed throughout thepermeable adhesive layer. In either case, the active agent is deliveredcontinuously from the reservoir or microcapsules through a membrane intothe active agent permeable adhesive, which is in contact with the skinor mucosa of the recipient. If the active agent is absorbed through theskin, a controlled and predetermined flow of the active agent isadministered to the recipient. In the case of microcapsules, theencapsulating agent may also function as the membrane.

In another device for transdermally administering the compounds inaccordance with the present invention, the pharmaceutically activecompound is contained in a matrix from which it is delivered in thedesired gradual, constant and controlled rate. The matrix is permeableto the release of the compound through diffusion or microporous flow.The release is rate controlling. Such a system, which requires nomembrane is described in U.S. Pat. No. 3,921,636. At least two types ofrelease are possible in these systems. Release by diffusion occurs whenthe matrix is non-porous. The pharmaceutically effective compounddissolves in and diffuses through the matrix itself. Release bymicroporous flow occurs when the pharmaceutically effective compound istransported through a liquid phase in the pores of the matrix.

As is true for most classes of compounds suitable for use as therapeuticagents, certain subgeneric groups and certain specific compounds arepreferred. Preferably, R₁, R₂, and R₃ are each methyl or ethyl, ormixtures thereof. Y is preferably hydrogen, --(CH₂)_(n) OR₅ wherein R₅is C₁₋₁₀ alkyl, and more preferably, methyl, hydroxy (C₁₋₆ alkyl andmore preferably alpha hydroxy C₁₋₆ alkyl, C₁₋₄ alkyl, or --(CH₂)_(N) NR₆R₆ ' wherein N preferably is zero. Preferably, Z is F. Q is preferablyC(O) or CH(OH). Y is preferably F. Z' is preferably H.

Specifically preferred compounds besides the compounds specificallyexemplified are those charted below as follows:

    ______________________________________                                        R.sub.1 R.sub.2 R.sub.3   Z'  Z     X   Y                                     ______________________________________                                        Methyl  Methyl  Methyl    H   F     F   Methyl                                Methyl  Methyl  Methyl    F   H     F   Methyl                                Methyl  Methyl  Methyl    H   F     F   Isopropyl                             Methyl  Methyl  Methyl    F   H     F   Isopropyl                             Methyl  Methyl  Ethyl     F   H     F   H                                     Methyl  Methyl  Ethyl     H   F     F   Methyl                                Methyl  Methyl  Ethyl     F   H     F   Methyl                                Methyl  Methyl  Ethyl     H   F     F   Isopropyl                             Methyl  Methyl  Ethyl     F   H     F   Isopropyl                             Methyl  Ethyl   Ethyl     H   F     F   H                                     Methyl  Ethyl   Ethyl     F   H     F   H                                     Methyl  Ethyl   Ethyl     H   F     F   Methyl                                Methyl  Ethyl   Ethyl     F   H     F   Methyl                                Methyl  Ethyl   Ethyl     H   F     F   Isopropyl                             Methyl  Ethyl   Ethyl     F   H     F   Isopropyl                             Methyl  Methyl  Propyl    H   F     F   H                                     Methyl  Methyl  Propyl    F   H     F   H                                     Methyl  Methyl  Propyl    H   F     F   Methyl                                Methyl  Methyl  Propyl    F   H     F   Methyl                                Methyl  Methyl  Propyl    H   F     F   Isopropyl                             Methyl  Methyl  Propyl    F   H     F   Isopropyl                             ______________________________________                                    

What is claimed is:
 1. A compound of the formula: ##STR22##stereoisomers or mixtures thereof, or pharmaceutically acceptable saltsthereof, wherein:each of Z and Z' are independently H or F, providedthat at least one of Z or Z' is F; Q is ##STR23## X is H, Br, Cl, F orCF₃ ; Y is H, OH, (C₁₋₆) alkyl, --(CH₂)_(m) OR₅, hydroxy(C₁₋₆)alkyl,--(CH₂)_(n) NR₆ R₆ ', azido, CN, CO₂ R₄, COR₆, SO₃ H, Br, Cl, F, NO₂ or--(CH₂)_(n) ' SIR₁ 'R₂ 'R₃ ', provided that when both Z and Z' are F,then Y is H or F; R₁, R₂, R₃, R₁ ', R₂ ' and R₃ ' are each independentlyC₁₋₁₀ alkyl or (CH₂)_(n") aryl; R₄ is H, C₁₋₁₀ alkyl, phenyl, benzyl orphenethyl; R₅ is H, C₁₋₁₀ alkyl, benzyl or phenethyl; R₆ and R₆ ' arehydrogen or C₁₋₁₀ alkyl; m is an integer of 0, 1, 2, 3 or 4; and n, n'and n" are each independently an integer of 0, 1 or
 2. 2. The compoundof claim 1 wherein each of R₁, R₂, R₃, R'₁, R'₂ and R'₃, when presentare independently methyl.
 3. The compound of claim 1 wherein Z is F. 4.The compound of claim 1 wherein Z' is H.
 5. The compound of claim 1wherein Q is C(O) or CH(OH).
 6. The compound of claim 1 wherein thecompound is 2,2,2-Trifluoro-1-(3-trimethylsilyl-6-fluoro)phenylethanone.
 7. The compound of claim 1 wherein the compound2,2,2-Trifluoro-1-(3-trimethylsilyl-6-fluoro)phenyl ethanol.
 8. Thecompound of claim 1 wherein the compound is2,2,2-Trifluoro-1-(2-fluoro-5-dimethylethylsilyl)phenyl ethanone.
 9. Thecompound of claim 1 wherein the compound2,2,2-Trifluoro-1-(2-fluoro-3-trimethylsilyl)phenyl ethanone.
 10. Thecompound of claim 1 wherein the compound is2,2,2-Trifluoro-1-(2,6-difluoro-3-trimethylsilyl)phenyl ethanone. 11.The compound of claim 1 wherein the compound is2,2,2-trifluoro-1-(2-fluoro-3-methoxymethyl-5-trimethylsilyl)phenylethanone.
 12. The compound of claim 1 wherein the compound is2,2,2-trifluoro-1-(2-fluoro-3-hydroxymethyl-5-trimethylsilyl)phenylethanone.
 13. The compound of claim 1 wherein the compound is2,2,2-trifluoro-1-(2-fluoro-3-n-butyl-5-trimethylsilyl)phenyl ethanone.14. The compound of claim 1 wherein the compound is2,2,2-trifluoro-1-(2-fluoro-3-amino-5-trimethylsilyl)phenyl ethanonehydrochloride.
 15. The process of making a compound of the formula:##STR24## stereoisomers or mixtures thereof, and pharmaceuticallyacceptable salts thereof, wherein:Q is ##STR25## X' is H, Br, Cl, or F:R₁, R₂, and R₃ are each independently C₁₋₁₀ alkyl or (CH₂)_(n") aryl; R₄is H, C₁₋₁₀ alkyl, phenyl, benzyl or phenethyl; m is an integer of 0, 1,2, 3 or 4; and n" is an integer of 0, 1 or 2;by converting the4-fluorotrialkylsilylphenyl compound: ##STR26## to the lithium salt, andthe reactant is combined with the ester XCF₂ CO₂ R, with X being ahalide and R being C₁₋₆ alkyl, or the acid lithum salt XCF₂ CO₂ Lifollowed by hydrolysis to produce the ketone, wherein X' is H, Br, Cl orF: ##STR27## and the ketone may be hydrolyzed to the alcohol which maybe subsequently esterified with an acyl chloride ClCOR₄.
 16. Acomposition comprising the compound of claim 1 and a pharmaceuticallyacceptable carrier.
 17. A method of treating a patient for degenerativedementias by administering to the patient an effective amount of thecompound of claim 1.